It has been known for some time that papillomaviruses are responsible for inducing diseases in many higher vertebrates, including humans. Papillomaviruses are small DNA viruses, nonenveloped, that replicate in the nucleus of squamous epithelial cells. They are spread widely throughout nature and are causative of epithelial proliferative lesions particularly, benign fibropapillomas, or as they are more commonly known warts. Papillomaviruses are also implicated in a number of cancers. To date there have been identified about 58 distinct human papillomaviruses, based on the extent and degree of relatedness of their genomes.
The clinical importance of warts varies considerably and determinative factors are the infecting viral type, the location of the wart, and factors unique to the host. For example, a wart located on the skin is often clinically insignificant, being self limiting. However, warts on the vocal cords may be life threatening as a result of respiratory obstruction. The vast majority of skin warts spontaneously regress within a few years after their initial appearance, but may persist for longer times. The exception is a rare life threatening papillomavirus disease termed epidermodyspasia verruciformis. In this disease, the infected individual does not experience spontaneous regression, but rather the infection may progress to a malignant stage. Orth, G. epitermodyspasia verruciformis, in: Salzman, N. P. Howley, P. M. Eds. the papovaviridae, vol. 2, N.Y.: Plenum Press 1987:199-243. The disease is present world-wide, but is rare and is often found among family members. Thus, genetic factors are thought to be involved in the etiology of the disease.
Papillomaviruses are also involved in producing sexually transmitted warts of the genital tract. There is reported to be well over a million cases in the United States alone. Beckter, T. M, Stone, K. M, Alexander, E. R., Genital Human Papillomavirus Infection: A Growing Concern Obstet Gynecol Clin North am 1987: 14:389-396.
As mentioned above, papillomavirus is thought to be responsible for several different types of cancer, including cervical cancer, of which there are about 500,000 new cases diagnosed yearly. Pto, R., Introduction: Geographic Patterns and Trends. in: Peto R., zur Hausen H. Eds. Virol Etiology of Cervical Cancer. BanBury Report 21. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1986;3-15. In addition to cervical cancer, papillomavirus has been implicated as a causative agent in nasal tumors, and various oral cancers.
Warts generally regress spontaneously, and thus patients that seek treatment do so for the relief of temporary pain or discomfort or for cosmetic reasons. Treatments for warts generally consist of the application of cryotherapy, or the use of one or more DNA synthesis inhibitors, or simply removing the warts surgically. Further treatments have consisted of the application of various interferons particularly against refractory genital warts. This approach has been partially successful with cure rates in the range of about 36% compared to spontaneous remissions of 3%.
Part of the explanation for the lack of unified treatment strategies for controlling or curing patients of papillomavirus infections is the inability to grow the virus in vitro, and thus develop a convenient and reliable assay to identify efficacious drugs. For the most part, the study of papillomavirus has come from the development of in vitro transformation assays that has facilitated the identification of viral functions involved in the induction of cellular proliferation. The prototype papillomavirus used in these studies has been bovine papillomavirus type I (BPV-1).
Papillomaviruses consist of double-stranded DNA of about 8,000 base pairs. Sequencing studies based on six animal and nine human papillomaviruses have revealed that the genomic organization of papillomaviruses is remarkably conserved. A key shared feature is that all of the viruses have open reading frames located on one strand of the viral DNA. There are approximately ten open reading frames that have been classified based on their position in the viral genome.
Using BPV-I, genetic studies have shown that papillomavirus plasmid replication relies upon the expression of particular viral early genes. The first such gene to be identified was the E2 trans-activator. Those molecules encoded by the E2 ORF stimulates transcription viral genes possibly through their interaction with enhancers in the so called long controlled region (LCR), a region in which there are no significant open reading frames, and which varies in size depending on the nature of the papillomavirus.
Many other papillomavirus transcriptional regulatory factors have been identified in addition to E2. E6 and E7 are involved in cellular transformation as is E5, which is the smallest of the known transforming proteins. In addition to the role that these early proteins play in viral transformation or transcription, there is data which suggest that they play indirect functions in viral plasmid replication. Indeed, of the early ORFs, only E3 and E4 have not been shown to be involved in viral plasmid replication. The E1 ORF encodes factors that are thought to be directly involved in plasmid replication and it is the largest ORF in the papillornavirus genome, and it is relatively highly conserved among those papillomaviruses whose genomes have been sequenced. At least two proteins are encoded by the E1 ORF. The 5' end of the E1 ORF encodes a protein with an apparent molecular weight of about 23,000 daltons while the protein encoded by 3' end encodes a 68,000 dalton protein. The latter protein is believed to play an essential role in viral DNA replication.